The present invention relates to a therapeutic agent for treating inflammatory diseases of eyes in which prostaglandin serves as a mediator of inflammation and more specifically to an eye drop for preventing and treating anterior ophthalmic inflammatory diseases observed, for instance, after the operation of cataract.
A non-steroid anti-inflammatory agent such as those containing sodium diclofenac, which shows its anti-inflammatory effect through the inhibition of the biosynthesis of prostaglandin as a mediator of the inflammation, is used not only for the treatment of inflammatory diseases by oral administration, but also for treating a variety of inflammatory diseases through local administration. In addition, it has also widely been used, in the form of an eye drop as a locally administered drug, for treating ophthalmic inflammatory diseases, in particular, anterior ophthalmic inflammatory symptoms after the operation of cataract and complications observed during and after the operation.
On the other hand, such a non-steroid anti-inflammatory eye drop is excellent in the anti-inflammatory action, but there has clinically been pointed out the occurrence of a side effect such as disorders of corneal epithelium at a frequency of about 1.6% (see a document attached to a medicine manufactured and sold by Wakamoto Pharmaceutical Co., Ltd., 1996). In other words, there has been desired for the development of a non-steroid anti-inflammatory eye drop, which is not accompanied with a high probability of causing disorders of corneal epithelium as a side effect.
As a result of the recent progress in researches, there have been pointed out, as sites of action of the non-steroid anti-inflammatory agent, inhibition of two enzymes, i.e., cyclooxygenase-1 (hereunder referred to as xe2x80x9cCOX-1xe2x80x9d) and cyclooxygenase-2 (hereunder referred to as xe2x80x9cCOX-2xe2x80x9d). It has been recognized that COX-1 serves to protect cells, while COX-2 is an enzyme involved in the inflammation. For this reason, there has been desired for the development of an anti-inflammatory agent, which can selectively inhibit COX-2 and has a low possibility of causing disorders of cells. The development of gastric ulcer as a side effect of a systemically administered anti-inflammatory agent has been studied in detail from such a standpoint discussed above. As a result, the roles of COX-1 and COX-2 have almost completely be elucidated and it has also been proved that the inhibition of COX-1 is involved in the development of gastric ulcer.
As has been described above, the mechanism of the action of these anti-inflammatory agents in the gastric ulcer has already been elucidated, but it has not yet been clear whether the disorders of corneal epithelium is caused by the same mechanism of action as that for the gastric ulcer or not. There has thus been desired for the development of a drug, which permits the distinct discrimination of the roles of COX-1 and COX-2 in such disorders of corneal epithelium and ophthalmic inflammatory diseases. Masferrer, JL et al. (Surv. Ophthalmol., 1997, 41 (suppl. 2):S35-40) reports that the anterior ophthalmic inflammation can be suppressed by a COX-2 inhibitor, but this article does not include any disclosure concerning the disorders of corneal epithelium. Miyake, K. (Clinical Ophthalmologists"" Reports, 1997, 51(11):190-191) suggests that the use of a selective COX-2-inhibitor can relieve disorders of corneal epithelium, but the article does not include any specific disclosure concerning means for solving the same.
The inventors of this invention have used a drug, which selectively inhibits COX-2, among non-steroid anti-inflammatory drugs as an eye drop, have investigated the effect thereof on anterior ophthalmic inflammatory diseases and disorder of ophthalmic cells and thus have completed the present invention.
More specifically, the present invention relates to an anti-inflammatory eye drop containing, as an effective component, a drug having high COX-2 selectivity. The inventors of this invention have tried to inspect compounds having COX-1 and COX-2 selectivity for an anti-inflammatory effect in vivo and an ability of damaging cells in vitro and as a result, have found that an anti-inflammatory eye drop containing, as an effective component, a drug having high COX-2 selectivity is excellent in the anti-inflammatory effect and in the alleviation of the cell-damage. Accordingly, it is an object of the present invention to provide an anti-inflammatory agent, which can alleviate any damage of cells such as corneal epithelial cells and conjunctival cells and an eye drop, which does not cause severe disorders of corneal epithelium.